55 results on '"ROMUALDI, PATRIZIA"'
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2. Communal nesting shapes the sex-dependent glutamatergic response to early life stress in the rat prefrontal cortex.
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Mottarlini, Francesca, Rizzi, Beatrice, Targa, Giorgia, Buzzelli, Valeria, Di Trapano, Melania, Rullo, Laura, Candeletti, Sanzio, Ciccocioppo, Roberto, Fattore, Liana, Romualdi, Patrizia, Fumagalli, Fabio, Trezza, Viviana, and Caffino, Lucia
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NEURAL transmission ,PREFRONTAL cortex ,METHYL aspartate receptors ,TEENAGE boys ,SOCIAL interaction ,SOCIAL isolation - Abstract
Introduction: Early social environment, either positive or negative, shapes the adult brain. Communal nesting (CN), a naturalistic setting in which 2-3 females keep their pups in a single nest sharing care-giving behavior, provides high level of peer interaction for pups. Early social isolation (ESI) from dam and siblings represents, instead, an adverse condition providing no peer interaction. Methods: We investigated whether CN (enrichment setting) might influence the response to ESI (impoverishment setting) in terms of social behavior and glutamate system in the medial prefrontal cortex (mPFC) of adult and adolescent male and female rats. Results: Pinning (a rewarding component of social play behavior) was significantly more pronounced in males than in females exposed to the combination of CN and ESI. CN sensitized the glutamate synapse in the mPFC of ESI-exposed male, but not female, rats. Accordingly, we observed (i) a potentiation of the glutamatergic neurotransmission in the mPFC of both adolescent and adult males, as shown by the recruitment of NMDA receptor subunits together with increased expression/activation of PSD95, SynCAM 1, Synapsin I and aCaMKII; (ii) a de-recruiting of NMDA receptors from active synaptic zones of same-age females, together with reduced expression/activation of the above-mentioned proteins, which might reduce the glutamate transmission. Whether similar sex-dependent glutamate homeostasis modulation occurs in other brain areas remains to be elucidated. Discussion: CN and ESI interact to shape social behavior and mPFC glutamate synapse homeostasis in an age- and sex-dependent fashion, suggesting that early-life social environment may play a crucial role in regulating the risk to develop psychopathology. [ABSTRACT FROM AUTHOR]
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- 2024
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3. Unburned Tobacco Smoke Affects Neuroinflammation-Related Pathways in the Rat Mesolimbic System.
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Morosini, Camilla, Vivarelli, Fabio, Rullo, Laura, Volino, Emilia, Losapio, Loredana Maria, Paolini, Moreno, Romualdi, Patrizia, Canistro, Donatella, and Candeletti, Sanzio
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TOBACCO smoke ,SMOKING ,COMPULSIVE behavior ,DRUG addiction ,NICOTINE ,TOBACCO use ,DOPAMINE - Abstract
Tobacco use disorder represents a significant public health challenge due to its association with various diseases. Despite awareness efforts, smoking rates remain high, partly due to ineffective cessation methods and the spread of new electronic devices. This study investigated the impact of prolonged nicotine exposure via a heat-not-burn (HnB) device on selected genes and signaling proteins involved in inflammatory processes in the rat ventral tegmental area (VTA) and nucleus accumbens (NAc), two brain regions associated with addiction to different drugs, including nicotine. The results showed a reduction in mRNA levels for PPARα and PPARγ, two nuclear receptors and anti-inflammatory transcription factors, along with the dysregulation of gene expression of the epigenetic modulator KDM6s, in both investigated brain areas. Moreover, decreased PTEN mRNA levels and higher AKT phosphorylation were detected in the VTA of HnB-exposed rats with respect to their control counterparts. Finally, significant alterations in ERK 1/2 phosphorylation were observed in both mesolimbic areas, with VTA decrease and NAc increase, respectively. Overall, the results suggest that HnB aerosol exposure disrupts intracellular pathways potentially involved in the development and maintenance of the neuroinflammatory state. Moreover, these data highlight that, similar to conventional cigarettes, HnB devices use affects specific signaling pathways shaping neuroinflammatory process in the VTA and NAc, thus triggering mechanisms that are currently considered as potentially relevant for the development of addictive behavior. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Effects of unburned tobacco smoke on inflammatory and oxidative mediators in the rat prefrontal cortex.
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Vivarelli, Fabio, Morosini, Camilla, Rullo, Laura, Losapio, Loredana Maria, Lacorte, Antonio, Sangiorgi, Stefano, Ghini, Severino, Fagiolino, Ivan, Franchi, Paola, Lucarini, Marco, Candeletti, Sanzio, Canistro, Donatella, Romualdi, Patrizia, and Paolini, Moreno
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TOBACCO smoke ,PREFRONTAL cortex ,SMOKING ,PEROXISOME proliferator-activated receptors ,CARCINOGENS ,NICOTINE ,INFLAMMATORY mediators - Abstract
Although the Food and Drug Administration has authorized the marketing of "heat-not-burn" (HnB) electronic cigarettes as a modified risk tobacco product (MRTP), toxicological effects of HnB smoke exposure on the brain are still unexplored. Here, paramagnetic resonance of the prefrontal cortex (PFC) of HnB-exposed rats shows a dramatic increase in reactive radical species (RRS) yield coupled with an inflammatory response mediated by NF-κB-target genes including TNF-a, IL-1ß, and IL-6 and the downregulation of peroxisome proliferator-activated receptor (PPAR) alpha and gamma expression. The PFC shows higher levels of 8-hydroxyguanosine, a marker of DNA oxidative damage, along with the activation of antioxidant machinery and DNA repair systems, including xeroderma pigmentosum group C (XPC) protein complex and 8-oxoguanine DNA glycosylase 1. HnB also induces the expression of drugmetabolizing enzymes such as CYP1A1, CYP2A6, CYP2B6, and CYP2E, particularly involved in the biotransformation of nicotine and several carcinogenic agents such as aldehydes and polycyclic aromatic hydrocarbons here recorded in the HnB stick smoke. Taken together, these effects, from disruption of redox homeostasis, inflammation, PPAR manipulation along with enhanced bioactivation of neurotoxicants, and upregulation of cMYC protooncogene to impairment of primary cellular defense mechanisms, suggest a possible increased risk of brain cancer. Although the HnB device reduces the emission of tobacco toxicants, our findings indicate that its consumption may carry a risk of potential adverse health effects, especially in non-smokers so far. Further studies are needed to fully understand the long-term effects of these devices. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Outcomes of early social experiences on glucocorticoid and endocannabinoid systems in the prefrontal cortex of male and female adolescent rats.
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Rullo, Laura, Losapio, Loredana Maria, Morosini, Camilla, Mottarlini, Francesca, Schiavi, Sara, Buzzelli, Valeria, Ascone, Fabrizio, Ciccocioppo, Roberto, Fattore, Liana, Caffino, Lucia, Fumagalli, Fabio, Romualdi, Patrizia, Trezza, Viviana, and Candeletti, Sanzio
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TEENAGE girls ,TEENAGE boys ,CANNABINOID receptors ,PREFRONTAL cortex ,GLUCOCORTICOIDS ,GLUCOCORTICOID receptors - Abstract
Social and emotional experiences differently shape individual’s neurodevelopment inducing substantial changes in neurobiological substrates and behavior, particularly when they occur early in life. In this scenario, the present study was aimed at (i) investigating the impact of early social environments on emotional reactivity of adolescent male and female rats and (ii) uncovering the underlying molecular features, focusing on the cortical endocannabinoid (eCB) and glucocorticoid systems. To this aim, we applied a protocol of environmental manipulation based on early postnatal socially enriched or impoverished conditions. Social enrichment was realized through communal nesting (CN). Conversely, an early social isolation (ESI) protocol was applied (post-natal days 14–21) to mimic an adverse early social environment. The two forms of social manipulation resulted in specific behavioral and molecular outcomes in both male and female rat offspring. Despite the combination of CN and ESI did not affect emotional reactivity in both sexes, the molecular results reveal that the preventive exposure to CN differently altered mRNA and protein expression of the main components of the glucocorticoid and eCB systems in male and female rats. In particular, adolescent females exposed to the combination of CN and ESI showed increased corticosterone levels, unaltered genomic glucocorticoid receptor, reduced cannabinoid receptor type-1 and fatty acid amide hydrolase protein levels, suggesting that the CN condition evokes different reorganization of these systems in males and females. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Communal nesting differentially attenuates the impact of pre-weaning social isolation on behavior in male and female rats during adolescence and adulthood.
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Bratzu, Jessica, Ciscato, Maria, Pisanu, Augusta, Talani, Giuseppe, Frau, Roberto, Porcu, Patrizia, Diana, Marco, Fumagalli, Fabio, Romualdi, Patrizia, Rullo, Laura, Trezza, Viviana, Ciccocioppo, Roberto, Sanna, Fabrizio, and Fattore, Liana
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ADOLESCENCE ,TEENAGE boys ,SOCIAL impact ,SOCIAL isolation ,ADULTS ,NEURAL inhibition ,TEENAGE girls - Abstract
Introduction: Early social isolation (ESI) disrupts neurodevelopmental processes, potentially leading to long-lasting emotional and cognitive changes in adulthood. Communal nesting (CN), i.e., the sharing of parental responsibilities between multiple individuals in a nest, creates a socially enriching environment known to impact social and anxiety-related behaviors. Methods: This study examines the effects of (i) the CN condition and of (ii) ESI during the 3rd week of life (i.e., pre-weaning ESI) on motor, cognitive, and emotional domains during adolescence and adulthood in male and female rats reared in the two different housing conditions, as well as (iii) the potential of CN to mitigate the impact of ESI on offspring. Results: We found that in a spontaneous locomotor activity test, females exhibited higher activity levels compared to males. In female groups, adolescents reared in standard housing (SH) condition spent less time in the center of the arena, suggestive of increased anxiety levels, while the CN condition increased the time spent in the center during adolescence, but not adulthood, independently from ESI. The prepulse inhibition (PPI) test showed a reduced PPI in ESI adolescent animals of both sexes and in adult males (but not in adult females), with CN restoring PPI in males, but not in adolescent females. Further, in the marble burying test SH-ESI adolescent males exhibited higher marble burying behavior than all other groups, suggestive of obsessive-compulsive traits. CN completely reversed this stress-induced effect. Interestingly, ESI and CN did not have a significant impact on burying behavior in adult animals of both sexes. Discussion: Overall, our findings (i) assess the effects of ESI on locomotion, sensorimotor gating, and compulsive-like behaviors, (ii) reveal distinct vulnerabilities of males and females within these domains, and (iii) show how early-life social enrichment may successfully counteract some of the behavioral alterations induced by early-life social stress in a sex-dependent manner. This study strengthens the notion that social experiences during early-life can shape emotional and cognitive outcomes in adulthood, and points to the importance of social enrichment interventions for mitigating the negative effects of early social stress on neurodevelopment. [ABSTRACT FROM AUTHOR]
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- 2023
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7. Effects of Different Opioid Drugs on Oxidative Status and Proteasome Activity in SH-SY5Y Cells.
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Rullo, Laura, Caputi, Francesca Felicia, Losapio, Loredana Maria, Morosini, Camilla, Posa, Luca, Canistro, Donatella, Vivarelli, Fabio, Romualdi, Patrizia, and Candeletti, Sanzio
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PROTEASOME inhibitors ,DRUG side effects ,OPIOIDS ,OPIOID receptors ,REACTIVE oxygen species ,SUPEROXIDE dismutase ,DRUGS ,DRUG efficacy - Abstract
Opioids are the most effective drugs used for the management of moderate to severe pain; however, their chronic use is often associated with numerous adverse effects. Some results indicate the involvement of oxidative stress as well as of proteasome function in the development of some opioid-related side effects including analgesic tolerance, opioid-induced hyperalgesia (OIH) and dependence. Based on the evidence, this study investigated the impact of morphine, buprenorphine or tapentadol on intracellular reactive oxygen species levels (ROS), superoxide dismutase activity/gene expression, as well as β2 and β5 subunit proteasome activity/biosynthesis in SH-SY5Y cells. Results showed that tested opioids differently altered ROS production and SOD activity/biosynthesis. Indeed, the increase in ROS production and the reduction in SOD function elicited by morphine were not shared by the other opioids. Moreover, tested drugs produced distinct changes in β2(trypsin-like) and β5(chymotrypsin-like) proteasome activity and biosynthesis. In fact, while prolonged morphine exposure significantly increased the proteolytic activity of both subunits and β5 mRNA levels, buprenorphine and tapentadol either reduced or did not alter these parameters. These results, showing different actions of the selected opioid drugs on the investigated parameters, suggest that a low µ receptor intrinsic efficacy could be related to a smaller oxidative stress and proteasome activation and could be useful to shed more light on the role of the investigated cellular processes in the occurrence of these opioid drug side effects. [ABSTRACT FROM AUTHOR]
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- 2022
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8. Chronic Trazodone and Citalopram Treatments Increase Trophic Factor and Circadian Rhythm Gene Expression in Rat Brain Regions Relevant for Antidepressant Efficacy.
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Carboni, Lucia, Rullo, Laura, Caputi, Francesca Felicia, Stamatakos, Serena, Candeletti, Sanzio, and Romualdi, Patrizia
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CIRCADIAN rhythms ,TRAZODONE ,HYPOTHALAMUS ,GENE expression ,ANTIDEPRESSANTS ,CITALOPRAM ,NUCLEUS accumbens - Abstract
Trazodone is an efficacious atypical antidepressant acting both as an SSRI and a 5HT2A and 5HT2C antagonist. Antagonism to H1-histaminergic and alpha1-adrenergic receptors is responsible for a sleep-promoting action. We studied long-term gene expression modulations induced by chronic trazodone to investigate the molecular underpinning of trazodone efficacy. Rats received acute or chronic treatment with trazodone or citalopram. mRNA expression of growth factor and circadian rhythm genes was evaluated by qPCR in the prefrontal cortex (PFCx), hippocampus, Nucleus Accumbens (NAc), amygdala, and hypothalamus. CREB levels and phosphorylation state were evaluated using Western blotting. BDNF levels were significantly increased in PFCx and hippocampus by trazodone and in the NAc and hypothalamus by citalopram. Likewise, TrkB receptor levels augmented in the PFCx after trazodone and in the amygdala after citalopram. FGF-2 and FGFR2 levels were higher after trazodone in the PFCx. The CREB phosphorylation state was increased by chronic trazodone in the PFCx, hippocampus, and hypothalamus. Bmal1 and Per1 were increased by both antidepressants after acute and chronic treatments, while Per2 levels were specifically augmented by chronic trazodone in the PFCx and NAc, and by citalopram in the PFCx, amygdala, and NAc. These findings show that trazodone affects the expression of neurotrophic factors involved in antidepressant responses and alters circadian rhythm genes implicated in the pathophysiology of depression, thus shedding light on trazodone's molecular mechanism of action. [ABSTRACT FROM AUTHOR]
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- 2022
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9. Supraspinal melatonin MT2 receptor agonism alleviates pain via a neural circuit that recruits mu opioid receptors.
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Posa, Luca, De Gregorio, Danilo, Lopez‐Canul, Martha, He, Qianzi, Darcq, Emmanuel, Rullo, Laura, Pearl‐Dowler, Leora, Luongo, Livio, Candeletti, Sanzio, Romualdi, Patrizia, Kieffer, Brigitte Lina, and Gobbi, Gabriella
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OPIOID receptors ,NEURAL circuitry ,G protein coupled receptors ,MELATONIN ,CANCER pain ,KNOCKOUT mice ,PAIN medicine - Abstract
Melatonin, through its G protein‐coupled receptor (GPCR) (MTNR1B gene) MT2, is implicated in analgesia, but the relationship between MT2 receptors and the opioid system remains elusive. In a model of rodent neuropathic pain (spared nerve injured [SNI]), the selective melatonin MT2 agonist UCM924 reversed the allodynia (a pain response to a non‐noxious stimulus), and this effect was nullified by the pharmacological blockade or genetic inactivation of the mu opioid receptor (MOR), but not the delta opioid receptor (DOR). Indeed, SNI MOR, but not DOR knockout mice, did not respond to the antiallodynic effects of the UCM924. Similarly, the nonselective opioid antagonist naloxone and the selective MOR antagonist D‐Phe‐Cys‐Tyr‐D‐Trp‐Orn‐Thr‐Pen‐Thr‐NH2 (CTOP) blocked the effects of UCM924 in SNI rats, but not the DOR antagonist naltrindole (NTI). Electrophysiological recordings in the rostral‐ventromedial medulla (RVM) revealed that the typical reduction of the firing activity of pronociceptive ON‐cells, and the enhancement of the firing of the antinociceptive OFF‐cells, induced by the microinjection of the MT2 agonist UCM924 into the ventrolateral periaqueductal gray (vlPAG) were blocked by MOR, but not DOR, antagonism. Immunohistochemistry studies showed that MT2 receptors are expressed in both excitatory (CaMKIIα+) and inhibitory (GAD65+) neuronal cell bodies in the vlPAG (~2.16% total), but not RVM. Only 0.20% of vlPAG neurons coexpressed MOR and MT2 receptors. Finally, UCM924 treatment induced an increase in the enkephalin precursor gene (PENK) in the PAG of SNI mice. Collectively, the melatonin MT2 receptor agonism requires MORs to exert its antiallodynic effects, mostly through an interneuronal circuit involving MOR and MT2 receptors. [ABSTRACT FROM AUTHOR]
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- 2022
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10. Current and Future Therapeutic Options in Pain Management: Multi-mechanistic Opioids Involving Both MOR and NOP Receptor Activation.
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Coluzzi, Flaminia, Rullo, Laura, Scerpa, Maria Sole, Losapio, Loredana Maria, Rocco, Monica, Billeci, Domenico, Candeletti, Sanzio, and Romualdi, Patrizia
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OPIOID receptors ,PAIN management ,OPIOID abuse ,OPIOIDS ,PEPTIDE receptors ,PEPTIDES ,PAIN threshold - Abstract
Opioids are widely used in chronic pain management, despite major concerns about their risk of adverse events, particularly abuse, misuse, and respiratory depression from overdose. Multi-mechanistic opioids, such as tapentadol and buprenorphine, have been widely studied as a valid alternative to traditional opioids for their safer profile. Special interest was focused on the role of the nociceptin opioid peptide (NOP) receptor in terms of analgesia and improved tolerability. Nociceptin opioid peptide receptor agonists were shown to reinforce the antinociceptive effect of mu opioid receptor (MOR) agonists and modulate some of their adverse effects. Therefore, multi-mechanistic opioids involving both MOR and NOP receptor activation became a major field of pharmaceutical and clinical investigations. Buprenorphine was re-discovered in a new perspective, as an atypical analgesic and as a substitution therapy for opioid use disorders; and buprenorphine derivatives have been tested in animal models of nociceptive and neuropathic pain. Similarly, cebranopadol, a full MOR/NOP receptor agonist, has been clinically evaluated for its potent analgesic efficacy and better tolerability profile, compared with traditional opioids. This review overviews pharmacological mechanisms of the NOP receptor system, including its role in pain management and in the development of opioid tolerance. Clinical data on buprenorphine suggest its role as a safer alternative to traditional opioids, particularly in patients with non-cancer pain; while data on cebranopadol still require phase III study results to approve its introduction on the market. Other bifunctional MOR/NOP receptor ligands, such as BU08028, BU10038, and AT-121, are currently under pharmacological investigations and could represent promising analgesic agents for the future. [ABSTRACT FROM AUTHOR]
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- 2022
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11. Early-life nicotine or cotinine exposure produces long-lasting sleep alterations and downregulation of hippocampal corticosteroid receptors in adult mice.
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Bastianini, Stefano, Lo Martire, Viviana, Alvente, Sara, Berteotti, Chiara, Matteoli, Gabriele, Rullo, Laura, Stamatakos, Serena, Silvani, Alessandro, Candeletti, Sanzio, Romualdi, Patrizia, Cohen, Gary, and Zoccoli, Giovanna
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STEROID receptors ,COTININE ,ADULTS ,HIPPOCAMPUS (Brain) ,MINERALOCORTICOID receptors - Abstract
Early-life exposure to environmental toxins like tobacco can permanently re-program body structure and function. Here, we investigated the long-term effects on mouse adult sleep phenotype exerted by early-life exposure to nicotine or to its principal metabolite, cotinine. Moreover, we investigated whether these effects occurred together with a reprogramming of the activity of the hippocampus, a key structure to coordinate the hormonal stress response. Adult male mice born from dams subjected to nicotine (NIC), cotinine (COT) or vehicle (CTRL) treatment in drinking water were implanted with electrodes for sleep recordings. NIC and COT mice spent significantly more time awake than CTRL mice at the transition between the rest (light) and the activity (dark) period. NIC and COT mice showed hippocampal glucocorticoid receptor (GR) downregulation compared to CTRL mice, and NIC mice also showed hippocampal mineralocorticoid receptor downregulation. Hippocampal GR expression significantly and inversely correlated with the amount of wakefulness at the light-to-dark transition, while no changes in DNA methylation were found. We demonstrated that early-life exposure to nicotine (and cotinine) concomitantly entails long-lasting reprogramming of hippocampal activity and sleep phenotype suggesting that the adult sleep phenotype may be modulated by events that occurred during that critical period of life. [ABSTRACT FROM AUTHOR]
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- 2021
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12. An Exploratory Pilot Study of Changes in Global DNA Methylation in Patients Undergoing Major Breast Surgery Under Opioid-Based General Anesthesia.
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Caputi, Francesca Felicia, Carboni, Lucia, Rullo, Laura, Alessandrini, Irene, Balzani, Eleonora, Melotti, Rita Maria, Romualdi, Patrizia, Candeletti, Sanzio, and Fanelli, Andrea
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DNA methylation ,BREAST surgery ,GENERAL anesthesia ,FENTANYL ,GENE expression ,DNA methyltransferases - Abstract
This study aimed to investigate DNA methylation levels in patients undergoing major breast surgery under opioid-based general anesthesia. Blood samples were collected from eleven enrolled patients, before, during and after anesthesia. PBMC were isolated and global DNA methylation levels as well as DNA methyltransferase (DNMT) and cytokine gene expression were assessed. DNA methylation levels significantly declined by 26%, reversing the direction after the end of surgery. Likewise, DNMT1a mRNA expression was significantly reduced at all time points, with lowest level of −68%. DNMT3a and DNMT3b decreased by 65 and 71%, respectively. Inflammatory cytokines IL6 and TNFα mRNA levels showed a trend for increased expression at early time-points to end with a significant decrease at 48 h after surgery. This exploratory study revealed for the first time intraoperative global DNA hypomethylation in patients undergoing major breast surgery under general anesthesia with fentanyl. The alterations of global DNA methylation here observed seem to be in agreement with DNMTs gene expression changes. Furthermore, based on perioperative variations of IL6 and TNFα gene expression, we hypothesize that DNA hypomethylation may occur as a response to surgical stress rather than to opiate exposure. [ABSTRACT FROM AUTHOR]
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- 2021
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13. Activation of Antioxidant and Proteolytic Pathways in the Nigrostriatal Dopaminergic System After 3,4-Methylenedioxymethamphetamine Administration: Sex-Related Differences.
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Costa, Giulia, Caputi, Francesca Felicia, Serra, Marcello, Simola, Nicola, Rullo, Laura, Stamatakos, Serena, Sanna, Fabrizio, Germain, Marc, Martinoli, Maria-Grazia, Candeletti, Sanzio, Morelli, Micaela, and Romualdi, Patrizia
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TYROSINE hydroxylase ,SUPEROXIDE dismutase ,ANTIOXIDANTS ,GLUTATHIONE peroxidase ,NEUROTOXICOLOGY ,GENE expression ,DOPAMINERGIC neurons - Abstract
3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is an amphetamine-related drug that may damage the dopaminergic nigrostriatal system. To investigate the mechanisms that sustain this toxic effect and ascertain their sex-dependence, we evaluated in the nigrostriatal system of MDMA-treated (4 × 20 mg/kg, 2 h apart) male and female mice the activity of superoxide dismutase (SOD), the gene expression of SOD type 1 and 2, together with SOD1/2 co-localization with tyrosine hydroxylase (TH)-positive neurons. In the same mice and brain areas, activity of glutathione peroxidase (GPx) and of β2/β5 subunits of the ubiquitin-proteasome system (UPS) were also evaluated. After MDMA, SOD1 increased in striatal TH-positive terminals, but not nigral neurons, of males and females, while SOD2 increased in striatal TH-positive terminals and nigral neurons of males only. Moreover, after MDMA, SOD1 gene expression increased in the midbrain of males and females, whereas SOD2 increased only in males. Finally, MDMA increased the SOD activity in the midbrain of females, without affecting GPx activity, decreased the β2/β5 activities in the striatum of males and the β2 activity in the midbrain of females. These results suggest that the mechanisms of MDMA-induced neurotoxic effects are sex-dependent and dopaminergic neurons of males could be more sensitive to SOD2- and UPS-mediated toxic effects. [ABSTRACT FROM AUTHOR]
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- 2021
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14. Nociceptive responses in melatonin MT2 receptor knockout mice compared to MT1 and double MT1/MT2 receptor knockout mice.
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Posa, Luca, Lopez‐Canul, Martha, Rullo, Laura, De Gregorio, Danilo, Dominguez‐Lopez, Sergio, Kaba Aboud, Matthew, Caputi, Francesca Felicia, Candeletti, Sanzio, Romualdi, Patrizia, and Gobbi, Gabriella
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KNOCKOUT mice ,G protein coupled receptors - Abstract
Melatonin, a neurohormone that binds to two G protein‐coupled receptors MT1 and MT2, is involved in pain regulation, but the distinct role of each receptor has yet to be defined. We characterized the nociceptive responses of mice with genetic inactivation of melatonin MT1 (MT1−/−), or MT2 (MT2−/−), or both MT1/MT2 (MT1−/−/MT2−/−) receptors in the hot plate test (HPT), and the formalin test (FT). In HPT and FT, MT1−/− display no differences compared to their wild‐type littermates (CTL), whereas both MT2−/− and MT1−/−/MT2−/− mice showed a reduced thermal sensitivity and a decreased tonic nocifensive behavior during phase 2 of the FT in the light phase. The MT2 partial agonist UCM924 induced an antinociceptive effect in MT1−/− but not in MT2−/− and MT1−/−/MT2−/− mice. Also, the competitive opioid antagonist naloxone had no effects in CTL, whereas it induced a decrease of nociceptive thresholds in MT2−/− mice. Our results show that the genetic inactivation of melatonin MT2, but not MT1 receptors, produces a distinct effect on nociceptive threshold, suggesting that the melatonin MT2 receptor subtype is selectively involved in the regulation of pain responses. [ABSTRACT FROM AUTHOR]
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- 2020
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15. Safe Use of Opioids in Chronic Kidney Disease and Hemodialysis Patients: Tips and Tricks for Non-Pain Specialists.
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Coluzzi, Flaminia, Caputi, Francesca Felicia, Billeci, Domenico, Pastore, Antonio Luigi, Candeletti, Sanzio, Rocco, Monica, and Romualdi, Patrizia
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CHRONIC kidney failure ,HEMODIALYSIS patients ,OPIOIDS ,DRUG side effects ,PAIN management - Abstract
In patients suffering from moderate-to-severe chronic kidney disease (CKD) or end-stage renal disease (ESRD), subjected to hemodialysis (HD), pain is very common, but often underestimated. Opioids are still the mainstay of severe chronic pain management; however, their prescription in CKD and HD patients is still significantly low and pain is often under-treated. Altered pharmacokinetics and the lack of clinical trials on the use of opioids in patients with renal impairment increase physicians' concerns in this specific population. This narrative review focused on the correct and safe use of opioids in patients with CKD and HD. Morphine and codeine are not recommended, because the accumulation of their metabolites may cause neurotoxic symptoms. Oxycodone and hydromorphone can be safely used, but adequate dosage adjustments are required in CKD. In dialyzed patients, these opioids should be considered as second-line agents and patients should be carefully monitored. According to different studies, buprenorphine and fentanyl could be considered first-line opioids in the management of pain in CKD; however, fentanyl is not appropriate in patients undergoing HD. Tapentadol does not need dosage adjustment in mild-to-moderate renal impairment conditions; however, no data are available on its use in ESRD. Opioid-related side effects may be exacerbated by common comorbidities in CKD patients. Opioid-induced constipation can be managed with peripherally-acting-μ-opioid-receptor-antagonists (PAMORA). Unlike the other PAMORA, naldemedine does not require any dose adjustment in CKD and HD patients. Accurate pain diagnosis, opioid titration and tailoring are mandatory to minimize the risks and to improve the outcome of the analgesic therapy. [ABSTRACT FROM AUTHOR]
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- 2020
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16. Modulation of sensitization processes in the management of pain and the importance of descending pathways: a role for tapentadol?
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Caraci, Filippo, Coluzzi, Flaminia, Marinangeli, Franco, Mercadante, Sebastiano, Rinonapoli, Giuseppe, Romualdi, Patrizia, Nicora, Mariaflavia, and Dickenson, Anthony H.
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PAIN management ,NOCICEPTIVE pain ,CHRONIC pain ,BACKACHE ,TREATMENT effectiveness ,BIOCHEMICAL mechanism of action ,THERAPEUTIC use of narcotics ,ANALGESICS ,NORADRENALINE ,CELL receptors ,ADRENERGIC uptake inhibitors - Abstract
Objective: This paper presents and discusses recent evidence on the pathophysiological mechanisms of pain. The role of tapentadol - an opioid characterized by an innovative mechanism of action (i.e. µ-opioid receptor [MOR] agonism and inhibition of noradrenaline [NA] reuptake [NRI]) - in the modulation of pain, and the most recent pharmacological evidence on this molecule (e.g. the µ-load concept) are also presented and commented upon.Methods: Narrative review.Results: Solid evidence has highlighted the importance of central sensitization in the transition from acute to chronic pain. In particular, the noradrenergic system holds a major role in limiting central sensitization and the progression to chronic pain. Therefore, pharmacological modulation of the noradrenergic system appears to be a well-grounded strategy for the control of chronic pain. Tapentadol is characterized by a to-date-unique mechanism of action, since it acts both as a MOR agonist and as an inhibitor of NA reuptake. The synergistic interaction of these two mechanisms allows a strong analgesic effect by acting on both ascending and descending pathways. Of note, the reduced µ-load of tapentadol limits the risk of opioid-related adverse events, such as gastrointestinal disturbances. Moreover, the NA component becomes predominant, at least, in some types of pain, with consequent specific clinical efficacy in the treatment of neuropathic and chronic pain.Conclusions: According to these characteristics, tapentadol appears suitable in the treatment of severe uncontrolled chronic pain characterized by both a nociceptive and a neuropathic component, such as osteoarthritis or back pain. [ABSTRACT FROM AUTHOR]
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- 2020
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17. NOP receptor antagonism reduces alcohol drinking in male and female rats through mechanisms involving the central amygdala and ventral tegmental area.
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Borruto, Anna Maria, Fotio, Yannick, Stopponi, Serena, Brunori, Gloria, Petrella, Michele, Caputi, Francesca Felicia, Romualdi, Patrizia, Candeletti, Sanzio, Narendran, Rajesh, Rorick‐Kehn, Linda M., Ubaldi, Massimo, Weiss, Friedbert, Ciccocioppo, Roberto, and Rorick-Kehn, Linda M
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ALCOHOL drinking ,ALCOHOLISM ,AMYGDALOID body ,NOCICEPTIN ,PHARMACOLOGY ,NUCLEUS accumbens ,LIMBIC system ,CELL receptors ,RATS ,DRUGS ,OPIOID peptides ,ANIMALS ,BRAIN stem - Abstract
Background and Purpose: Nociceptin/orphanin FQ (N/OFQ) peptide and its cognate receptor (NOP) are widely expressed in mesolimbic brain regions where they play an important role in modulating reward and motivation. Early evidence suggested that NOP receptor activation attenuates the rewarding effects of drugs of abuse, including alcohol. However, emerging data indicate that NOP receptor blockade also effectively attenuates alcohol drinking and relapse. To advance our understanding of the role of the N/OFQ-NOP receptor system in alcohol abuse, we examined the effect of NOP receptor blockade on voluntary alcohol drinking at the neurocircuitry level.Experimental Approach: Using male and female genetically selected alcohol-preferring Marchigian Sardinian (msP) rats, we initially evaluated the effects of the selective NOP receptor antagonist LY2817412 (3, 10, and 30 mg·kg-1 , p.o.) on alcohol consumption in a two-bottle free-choice paradigm. We then microinjected LY2817412 (3 and 6 μg·μl-1 per rat) in the central nucleus of the amygdala (CeA), ventral tegmental area (VTA), and nucleus accumbens (NAc).Key Results: Peripheral LY2817412 administration dose-dependently and selectively reduced voluntary alcohol intake in male and female msP rats. Central injections of LY2817412 markedly attenuated voluntary alcohol intake in both sexes following administration in the CeA and VTA but not in the NAc.Conclusion and Implications: The present results revealed that the CeA and VTA are neuroanatomical substrates that mediate the effects of NOP receptor antagonism on alcohol consumption. Overall, our findings support the potential of NOP receptor antagonism as a treatment strategy to attenuate alcohol use and addiction. [ABSTRACT FROM AUTHOR]- Published
- 2020
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18. Activation of PPARγ Attenuates the Expression of Physical and Affective Nicotine Withdrawal Symptoms through Mechanisms Involving Amygdala and Hippocampus Neurotransmission.
- Author
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Domi, Esi, Caputi, Francesca Felicia, Romualdi, Patrizia, Domi, Ana, Scuppa, Giulia, Candeletti, Sanzio, Atkins, Alison, Heilig, Markus, Demopulos, Gregory, Gaitanaris, George, Ciccocioppo, Roberto, and Ubaldi, Massimo
- Subjects
NICOTINE ,PEROXISOME proliferator-activated receptors ,DRUG withdrawal symptoms ,AMYGDALOID body ,NEURAL transmission ,HIPPOCAMPUS (Brain) - Abstract
An isoform of peroxisome proliferator-activated receptors (PPARs), PPARγ, is the receptor for the thiazolidinedione class of antidiabetic medications including pioglitazone. Neuroanatomical data indicate PPARγ localization in brain areas involved in drug addiction. Preclinical and clinical data have shown that pioglitazone reduces alcohol and opioid self-administration, relapse to drug seeking, and plays a role in emotional responses. Here, we investigated the behavioral effect of PPARγ manipulation on nicotine withdrawal in male Wistar rats and in male mice with neuron-specific PPARγ deletion (PPARγ
(-/-) ) and their littermate wild-type (PPARγ(+/+) ) controls. Real-time quantitative RT-PCR and RNAscope in situ hybridization assays were used for assessing the levels of expression and cell-type localization of PPARγ during nicotine withdrawal. Brain site-specific microinjections of the PPARγ agonist pioglitazone were performed to explore the role of this system on nicotine withdrawal at a neurocircuitry level. Results showed that activation of PPARy by pioglitazone abolished the expression of somatic and affective nicotine withdrawal signs in rats and in (PPARγ(+/+) mice. This effect was blocked by the PPARγ antagonist GW9662. During early withdrawal and protracted abstinence, the expression of PPARy increased in GABAergic and glutamatergic cells of the amygdala and hippocampus, respectively. Hippocampal microinjections of pioglitazone reduced the expression of the physical signs of withdrawal, whereas excessive anxiety associated with protracted abstinence was prevented by pioglitazone microinjection into the amygdala. Our results demonstrate the implication of the neuronal PPARγ in nicotine withdrawal and indicates that activation of PPARγ may offer an interesting strategy for smoking cessation. [ABSTRACT FROM AUTHOR]- Published
- 2019
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19. Novel insights on the management of pain: highlights from the 'Science of Relief' meeting.
- Author
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Anand, Praveen, Dickenson, Anthony, Finco, Gabriele, Marinangeli, Franco, Polati, Enrico, Romualdi, Patrizia, Tzschentke, Thomas M, and Canonico, Pier Luigi
- Published
- 2019
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20. Pharmacological rationale for tapentadol therapy: a review of new evidence.
- Author
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Romualdi, Patrizia, Grilli, Mariagrazia, Canonico, Pier Luigi, Collino, Massimo, and Dickenson, Anthony H
- Subjects
NOCICEPTIVE pain ,CANCER pain ,CHRONIC pain ,CHRONIC pain treatment ,ETIOLOGY of cancer - Abstract
Chronic pain could be considered as a neurological disorder. Therefore, appropriate selection of the therapy, which should consider the pathophysiological mechanisms of pain, can result in a successful analgesic outcome. Tapentadol is an analgesic drug which acts both as a μ-opioid receptor (MOR) agonist and as a noradrenaline reuptake inhibitor (NRI), thereby generating a synergistic action in terms of analgesic efficacy, but not for the burden of adverse effects. Therefore, tapentadol can be defined as the first "MOR-NRI" drug. This molecule holds the potential to address at least some of the current limitations of analgesic therapy due to its unique mechanism of action and has shown to be safe and effective in the treatment of chronic pain of cancer and noncancer etiologies including nociceptive, neuropathic and mixed pain. In particular, the MOR component of tapentadol activity predominantly allows for analgesia in nociceptive pain; on the other hand, the NRI component contributes, now in a predominant manner, for analgesic efficacy in cases of neuropathic pain states. This paper will discuss recent pieces of evidence on the pathophysiology of pain, the background on tapentadol and then present some new studies on how the unique mechanism of action of tapentadol provides a key role in its analgesic efficacy in a number of pain states and with a favorable safety profile. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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21. Effetto della formulazione di fentanyl con sistema di rilascio OraVescent®: veloce ed efficace nel dolore da BTCP.
- Author
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Romualdi, Patrizia and Rullo, Laura
- Published
- 2022
22. The standardized Withania somnifera Dunal root extract alters basal and morphineinduced opioid receptor gene expression changes in neuroblastoma cells.
- Author
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Caputi, Francesca Felicia, Acquas, Elio, Kasture, Sanjay, Ruiu, Stefania, Candeletti, Sanzio, and Romualdi, Patrizia
- Subjects
GENE expression ,NEUROBLASTOMA ,PLANT roots ,PLANT extracts ,DATA analysis - Abstract
Background: Behavioral studies demonstrated that the administration of Withania somnifera Dunal roots extract (WSE), prolongs morphine-elicited analgesia and reduces the development of tolerance to the morphine's analgesic effect; however, little is known about the underpinning molecular mechanism(s). In order to shed light on this issue in the present paper we explored whether WSE promotes alterations of μ (MOP) and nociceptin (NOP) opioid receptors gene expression in neuroblastoma SH-SY5Y cells. Methods: A range of WSE concentrations was preliminarily tested to evaluate their effects on cell viability. Subsequently, the effects of 5 h exposure to WSE (0.25, 0.50 and 1.00 mg/ml), applied alone and in combination with morphine or naloxone, on MOP and NOP mRNA levels were investigated. Results: eData analysis revealed that morphine decreased MOP and NOP receptor gene expression, whereas naloxone elicited their up-regulation. In addition, pre-treatment with naloxone prevented the morphine-elicited gene expression alterations. Interestingly, WSE was able to: a) alter MOP but not NOP gene expression; b) counteract, at its highest concentration, morphine-induced MOP down-regulation, and c) hamper naloxoneinduced MOP and NOP up-regulation. Conclusion: Present in-vitro data disclose novel evidence about the ability of WSE to influence MOP and NOP opioid receptors gene expression in SH-SY5Y cells. Moreover, our findings suggest that the in-vivo modulation of morphine-mediated analgesia by WSE could be related to the hindering of morphine-elicited opioid receptors down-regulation here observed following WSE pre-treatment at its highest concentration. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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23. The challenge of perioperative pain management in opioid-tolerant patients.
- Author
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Coluzzi, Flaminia, Bifulco, Francesca, Cuomo, Arturo, Dauri, Mario, Leonardi, Claudio, Melotti, Rita Maria, Natoli, Silvia, Romualdi, Patrizia, Savoia, Gennaro, and Corcione, Antonio
- Subjects
OPIOIDS ,HYPERALGESIA ,CHRONIC pain ,ANESTHESIOLOGISTS ,NALTREXONE ,PATIENTS - Abstract
The increasing number of opioid users among chronic pain patients, and opioid abusers among the general population, makes perioperative pain management challenging for health care professionals. Anesthesiologists, surgeons, and nurses should be familiar with some pharmacological phenomena which are typical of opioid users and abusers, such as tolerance, physical dependence, hyperalgesia, and addiction. Inadequate pain management is very common in these patients, due to common prejudices and fears. The target of preoperative evaluation is to identify comorbidities and risk factors and recognize signs and symptoms of opioid abuse and opioid withdrawal. Clinicians are encouraged to plan perioperative pain medications and to refer these patients to psychiatrists and addiction specialists for their evaluation. The aim of this review was to give practical suggestions for perioperative management of surgical opioid-tolerant patients, together with schemes of opioid conversion for chronic pain patients assuming oral or transdermal opioids, and patients under maintenance programs with methadone, buprenorphine, or naltrexone. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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24. Assessment and treatment of breakthrough cancer pain: from theory to clinical practice.
- Author
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Vellucci, Renato, Mediati, Rocco Domenico, Gasperoni, Silvia, Mammucari, Massimo, Marinangeli, Franco, and Romualdi, Patrizia
- Subjects
ANALGESIA ,CANCER complications ,BREAKTHROUGH pain ,CANCER pain ,CANCER treatment ,THERAPEUTICS - Abstract
Breakthrough cancer pain (BTcP) is a common condition in oncological patients. However, its management is still suboptimal. Improved knowledge of BTcP and its management in clinical practice may have immediate importance for all physicians involved in the supportive care of cancer patients. This review critically discusses the most important concepts for the correct diagnosis of BTcP and presents some intriguing cases of the management of this condition in clinical practice. Overall, the most appropriate therapeutic choice appears to be a rapid-onset opioid (ROO), and in particular, the nasal route of administration is the quickest and most convenient mode of administration for the management of BTcP, especially when the patient needs rapid resolution of pain. To this end, intranasal fentanyl spray may have a particular relevance in clinical practice. Future research should focus on accepted definitions of BTcP to investigate the optimal management of this highly heterogeneous pain condition. Therapeutic decision-making of patients, clinicians, and payers will likely be driven from results of welldesigned clinical trials of ROOs. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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25. Mystic Acetaldehyde: The Never-Ending Story on Alcoholism.
- Author
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Peana, Alessandra T., Sánchez-Catalán, María J., Hipólito, Lucia, Rosas, Michela, Porru, Simona, Bennardini, Federico, Romualdi, Patrizia, Caputi, Francesca F., Candeletti, Sanzio, Polache, Ana, Granero, Luis, and Acquas, Elio
- Subjects
PHYSIOLOGICAL effects of acetaldehyde ,ALCOHOLISM ,PHYSIOLOGICAL effects of dopamine ,SALSOLINOL ,DRUG administration - Abstract
After decades of uncertainties and drawbacks, the study on the role and significance of acetaldehyde in the effects of ethanol seemed to have found its main paths. Accordingly, the effects of acetaldehyde, after its systemic or central administration and as obtained following ethanol metabolism, looked as they were extensively characterized. However, almost 5 years after this research appeared at its highest momentum, the investigations on this topic have been revitalized on at least three main directions: (1) the role and the behavioral significance of acetaldehyde in different phases of ethanol self-administration and in voluntary ethanol consumption; (2) the distinction, in the central effects of ethanol, between those arising from its non-metabolized fraction and those attributable to ethanol-derived acetaldehyde; and (3) the role of the acetaldehyde-dopamine condensation product, salsolinol. The present review article aims at presenting and discussing prospectively the most recent data accumulated following these three research pathways on this never-ending story in order to offer the most up-to-date synoptic critical view on such still unresolved and exciting topic. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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- View/download PDF
26. Combined exposure to agriculture pesticides, paraquat and maneb, induces alterations in the N/OFQ-NOPr and PDYN/KOPr systems in rats: Relevance to sporadic Parkinson's disease.
- Author
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Bastías‐Candia, Sussy, Di Benedetto, Manuela, D'Addario, Claudio, Candeletti, Sanzio, and Romualdi, Patrizia
- Subjects
PESTICIDES ,PARKINSON'S disease ,BRAIN diseases ,LABORATORY rats ,PARAQUAT ,BIPYRIDINIUM compounds ,MANEB - Abstract
ABSTRACT Despite several years of research, the aetiology of Parkinson's disease (PD) is quite far from being solved. In PD, as well as in other neurodegenerative disorders, it has been proposed that the combination of multiple factors might contribute to the onset of the disease. Indeed, several authors have suggested that environmental factors, such as pollutants and chemicals, might be associated with the onset of several neurodegenerative disorders. On the other hand, several studies have described that the nociceptin/orphanin-NOP and prodynorphin-KOP opioid systems are implicated in the pathology of Parkinson's disease. Considering the nonrestricted commercial availability and common use of several pesticides, such as paraquat and maneb, in agriculture of less developed countries, the aim of our study was to investigate the involvement of nociceptin/orphanin-NOP and prodynorphin-KOP systems in a chronic paraquat and maneb animal model of Parkinson's disease. Our results showed that after paraquat/maneb (5/15 mg kg
−1 ) treatment, a significant reduction in tyrosine hydroxylase (TH) levels, the rate-limiting enzyme for dopamine synthesis, was observed. Also, the association of paraquat and maneb (5/15 mg kg−1 ) induced an increase in nociceptin/orphanin and a decrease of prodynorphin gene expression levels in the substantia nigra with a down-regulation of NOP and KOP receptors after both treatments in the substantia nigra and caudate putamen. These data further confirm that paraquat and maneb toxicity can modulate gene expression of the nociceptin/orphanin-NOP receptor and prodynorphin-KOP receptor systems in the substantia nigra and caudate putamen, offering further support to the hypothesis that chronic exposure to these agrochemicals might be implicated in the mechanisms underlying sporadic Parkinson's disease. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 656-663, 2015. [ABSTRACT FROM AUTHOR]- Published
- 2015
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27. Opioid Receptor Gene Expression in Human Neuroblastoma SH-SY5Y Cells Following Tapentadol Exposure.
- Author
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Caputi, Francesca, Carretta, Donatella, Tzschentke, Thomas, Candeletti, Sanzio, and Romualdi, Patrizia
- Abstract
Recent studies showed that combination of mu opioid receptor (MOP) agonism and monoamine reuptake inhibition may improve the therapeutic effect of opioids by reducing requirement for MOP activation. Tapentadol, showing such a combined mechanism of action, exhibits delayed analgesic tolerance development compared to pure MOP agonists. Here we investigated how opioid receptors are regulated following different schedules (two ranges of concentrations for 24 and 48 h) of tapentadol exposure in vitro in SH-SY5Y cells. MOP and nociceptin/orphaninFQ (NOP) receptor gene expressions were quantified using qReal-Time PCR. Moreover, studies were performed in U2 cells to assess tapentadol effect on MOP internalization compared with morphine and DAMGO. Ten and 100 nM tapentadol for 48 h induced a significant increase of MOP gene expression; cells exposed to 100 μM tapentadol for 24 and 48 h showed a significant increase of MOP mRNA levels. NOP gene expression showed a significant decrease following tapentadol at all low concentrations used after 24 h and at high concentrations (45 and 60 μM) after 24 h and (60 μM) after 48 h. Differently from DAMGO, tapentadol or morphine showed no effects on MOP internalization. This study suggests that tapentadol affects MOP and NOP gene expression and MOP internalization showing a pattern distinct from classical MOP agonists. Whether these differences can explain the improved therapeutic profile of tapentadol remains to be investigated. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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28. Morphine and Fentanyl Differently Affect MOP and NOP Gene Expression in Human Neuroblastoma SH-SY5Y Cells.
- Author
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Caputi, Francesca, Lattanzio, Francesca, Carretta, Donatella, Mercatelli, Daniela, Candeletti, Sanzio, and Romualdi, Patrizia
- Abstract
Morphine is widely used for the treatment of severe acute and chronic pain, but long-term therapy rapidly leads to tolerance. Morphine effects are mediated by μ opioid receptor (MOP) activation as well as for fentanyl that, in contrast to morphine, induces less tolerance to analgesia. The mechanisms underlying opioid tolerance involve complex processes, such as MOP desensitization, internalization, and/or changes of gene expression. The development of morphine tolerance also involves adaptive changes of the anti-opioid nociceptin/orphanin FQ-nociceptin receptor system, as suggested by the reduction of morphine tolerance in nociceptin opioid receptor (NOP) knockout mice. The aim of the present study was to investigate the MOP and NOP gene expression in the SH-SY5Y cells following morphine and fentanyl exposure. Results showed that cell exposure to 10 μM morphine for 5 h induced a significant decrease of MOP and NOP gene expression and that the MOP downregulation was reverted by the pretreatment with naloxone. Conversely, SH-SY5Y cells exposed to 0.1 and 1 μM fentanyl for 5 and 72 h showed a significant MOP upregulation, also reverted by naloxone pretreatment. Fentanyl induced no changes of NOP gene expression. The present findings showed a different effect by morphine and fentanyl on MOP mRNA levels that contributes to define the role of MOP gene expression changes in the mechanisms underlying the tolerance. Morphine also triggers an altered NOP-related signaling confirming that the nociceptin/orphanin FQ-nociceptin receptor system also plays a significant role in the development of morphine tolerance. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
29. Selection of nutraceutical compounds as COX inhibitors by molecular topology.
- Author
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Gálvez-Llompart, María, Zanni, Riccardo, Romualdi, Patrizia, and García-Domenech, Ramón
- Abstract
QSAR based on molecular topology (MT) has proven to be a very efficient method in drug design and discovery. In this study, some models based on MT have been obtained by linear discriminant analysis (LDA) and artificial neural networks (ANN). Later on, the models were applied to the search of new cyclooxygenase (COX) inhibitors showing anti-inflammatory activity. Moreover, an external validation test has been carried out, yielding 80 % of correct classification within the active compounds and 78.6 % within the inactive. The results from ANN showed a correct classification percentage above 85 % for the test set and of 90 % for the external validation set. The accuracy of the models was also checked using the literature data, upon the carrageenan-induced mice paw edema test. In this case, the models were capable to classify correctly four out of five active compounds as well as two out of the two inactive ones, which enabled the models' optimization. Finally, a virtual screening on a nutraceutical database was performed, from which ten compounds were selected for their potential COX inhibitory activity. The results shown here enhance MT's role as a very efficient tool for the discovery of new COX inhibitors with potential anti-inflammatory activity. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
30. Different alcohol exposures induce selective alterations on the expression of dynorphin and nociceptin systems related genes in rat brain.
- Author
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D'Addario, Claudio, Caputi, Francesca F., Rimondini, Roberto, Gandolfi, Ottavio, Del Borrello, Elia, Candeletti, Sanzio, and Romualdi, Patrizia
- Subjects
ALCOHOLISM ,NOCICEPTIN ,MOLECULAR genetics ,LABORATORY rats ,BRAIN function localization ,MAGNETIC resonance imaging of the brain - Abstract
ABSTRACT Molecular mechanisms of adaptive transformations caused by alcohol exposure on opioid dynorphin and nociceptin systems have been investigated in the rat brain. Alcohol was intragastrically administered to rats to resemble human drinking with several hours of exposure: water or alcohol (20% in water) at a dose of 1.5 g/kg three times daily for 1 or 5 days. The development of tolerance and dependence were recorded daily. Brains were dissected 30 minutes (1- and 5-day groups) or 1, 3 or 7 days after the last administration for the three other 5-day groups (groups under withdrawal). Specific alterations in opioid genes expression were ascertained. In the amygdala, an up-regulation of prodynorphin and pronociceptin was observed in the 1-day group; moreover, pronociceptin and the kappa opioid receptor mRNAs in the 5-day group and both peptide precursors in the 1-day withdrawal group were also up-regulated. In the prefrontal cortex, an increase in prodynorhin expression in the 1-day group was detected. These data indicate a relevant role of the dynorphinergic system in the negative hedonic states associated with multiple alcohol exposure. The pattern of alterations observed for the nociceptin system appears to be consistent with its role of functional antagonism towards the actions of ethanol associated with other opioid peptides. Our findings could help to the understanding of how alcohol differentially affects the opioid systems in the brain and also suggest the dynorphin and nociceptin systems as possible targets for the treatment and/or prevention of alcohol dependence. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
31. Modification of anxiety-like behaviors by nociceptin/orphanin FQ ( N/ OFQ) and time-dependent changes in N/ OFQ-NOP gene expression following ethanol withdrawal.
- Author
-
Aujla, Harinder, Cannarsa, Rosalia, Romualdi, Patrizia, Ciccocioppo, Roberto, Martin‐Fardon, Rémi, and Weiss, Friedbert
- Subjects
ANXIETY ,NOCICEPTIN ,GENE expression ,MOLECULAR genetics ,DEVELOPMENTAL stability (Genetics) ,GENETIC regulation ,ETHANOL - Abstract
Anxiety is a key consequence of ethanol withdrawal and important risk factor for relapse. The neuropeptide nociceptin/orphanin FQ ( N/ OFQ) or agonists at this peptide's receptor ( NOP) exert anxiolytic-like and antistress actions. N/ OFQ dysfunction has been linked to both a high-anxiety behavioral phenotype and excessive ethanol intake. Recent studies suggest a possible link between genetic polymorphisms of the NOP transcript and alcoholism. Thus, in the present study, the effects of intracerebroventricularly administered N/ OFQ were tested for modification of anxiety-like behaviors, using the shock-probe defensive burying and elevated plus-maze tests, in ethanol-dependent versus non-dependent rats, 1 and 3 weeks following termination of ethanol exposure. Additionally, prepro- N/ OFQ (pp N/ OFQ) and NOP receptor gene expression was measured in the central nucleus of the amygdala, in the bed nucleus of the stria terminalis and in the lateral hypothalamus at the same timepoints in separate subjects. One week post-ethanol, N/ OFQ dose-dependently attenuated elevated anxiety-like behavior in ethanol-dependent rats and produced anxiolytic-like effects in non-dependent controls in both behavioral tests. However, 3 weeks post-ethanol, N/ OFQ altered behavior consistent with anxiogenic-like actions in ethanol-dependent rats but continued to exert anxiolytic-like actions in non-dependent controls. These findings were paralleled by ethanol history-dependent changes of pp N/ OFQ and NOP gene expression that showed a distinctive time course in the examined brain structures. The results demonstrate that ethanol dependence and withdrawal are associated with neuroadaptive changes in the N/ OFQ- NOP system, suggesting a role of this neuropeptidergic pathway as a therapeutic target for the treatment of alcohol abuse. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
32. Ethanol Induces Epigenetic Modulation of Prodynorphin and Pronociceptin Gene Expression in the Rat Amygdala Complex.
- Author
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D'Addario, Claudio, Caputi, Francesca, Ekström, Tomas, Di Benedetto, Manuela, Maccarrone, Mauro, Romualdi, Patrizia, and Candeletti, Sanzio
- Abstract
Several studies demonstrated the role of the endogenous opioid system in the development of susceptibility to alcohol dependence. Recently, we reported that binge intragastric administration of ethanol induces selective alterations of pronociceptin and prodynorphin gene expression in the rat amygdala complex depending on the days of exposures and on the development of tolerance and dependence. The aim of the present study was to investigate the potential epigenetic mechanisms leading to these alcohol-induced changes in gene expression. Specific histone modifications and DNA methylation at opioid peptide precursor promoters were analyzed by chromatin immunoprecipitation and real-time methylation-specific PCR, respectively. We found a linkage between gene expression alterations and epigenetic modulation at pronociceptin and prodynorphin promoters following alcohol treatment. In animals treated for 1 day, we observed a reversed correlation, with a decrease of histone 3 lysine 27 trimethylation (repressive mark) and an increase of histone 3 lysine 9 acetylation (activating mark), associated with both gene expression up-regulation. In rats treated with alcohol for up to 5 days, we found an increase in histone 3 lysine 9 acetylation in the pronociceptin promoter providing further evidence of the already proposed possible role for histone deacetylases for addiction treatment. No significant alterations in DNA methylation and histone 3 lysine 4 trimethylation following different alcohol exposures were present, suggesting the selectivity of epigenetic effects induced by alcohol. These data demonstrate that ethanol induces selective epigenetic changes, thus better defining the role of opioid peptides in the ethanol-induced effects in the amygdala complex. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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- View/download PDF
33. Selective DNA Methylation of BDNF Promoter in Bipolar Disorder: Differences Among Patients with BDI and BDII.
- Author
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D'Addario, Claudio, Dell'Osso, Bernardo, Palazzo, Maria Carlotta, Benatti, Beatrice, Lietti, Licia, Cattaneo, Elisabetta, Galimberti, Daniela, Fenoglio, Chiara, Cortini, Francesca, Scarpini, Elio, Arosio, Beatrice, Di Francesco, Andrea, Di Benedetto, Manuela, Romualdi, Patrizia, Candeletti, Sanzio, Mari, Daniela, Bergamaschini, Luigi, Bresolin, Nereo, Maccarrone, Mauro, and Altamura, A Carlo
- Subjects
DNA methylation ,BIPOLAR disorder ,GENE expression ,GENETIC regulation ,PSYCHIATRIC drugs - Abstract
The etiology of bipolar disorder (BD) is still poorly understood, involving genetic and epigenetic mechanisms as well as environmental contributions. This study aimed to investigate the degree of DNA methylation at the promoter region of the brain-derived neurotrophic factor (BDNF) gene, as one of the candidate genes associated with major psychoses, in peripheral blood mononuclear cells isolated from 94 patients with BD (BD I=49, BD II=45) and 52 healthy controls. A significant BDNF gene expression downregulation was observed in BD II 0.53±0.11%; P<0.05), but not in BD I (1.13±0.19%) patients compared with controls (CONT: 1±0.2%). Consistently, an hypermethylation of the BDNF promoter region was specifically found in BD II patients (CONT: 24.0±2.1%; BDI: 20.4±1.7%; BDII: 33.3±3.5%, P<0.05). Of note, higher levels of DNA methylation were observed in BD subjects on pharmacological treatment with mood stabilizers plus antidepressants (34.6±4.2%, predominantly BD II) compared with those exclusively on mood-stabilizing agents (21.7±1.8%; P<0.01, predominantly BD I). Moreover, among the different pharmacological therapies, lithium (20.1±3.8%, P<0.05) and valproate (23.6±2.9%, P<0.05) were associated with a significant reduction of DNA methylation compared with other drugs (35.6±4.6%). Present findings suggest selective changes in DNA methylation of BDNF promoter in subjects with BD type II and highlight the importance of epigenetic factors in mediating the onset and/or susceptibility to BD, providing new insight into the mechanisms of gene expression. Moreover, they shed light on possible mechanisms of action of mood-stabilizing compounds vs antidepressants in the treatment of BD, pointing out that BDNF regulation might be a key target for their effects. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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34. ∆-Tetrahydrocannabinol Decreases NOP Receptor Density and mRNA Levels in Human SH-SY5Y Cells.
- Author
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Cannarsa, Rosalia, Carretta, Donatella, Lattanzio, Francesca, Candeletti, Sanzio, and Romualdi, Patrizia
- Abstract
Several studies demonstrated a cross-talk between the opioid and cannabinoid system. The NOP receptor and its endogenous ligand nociceptin/orphanin FQ represent an opioid-related functional entity that mediates some non-classical opioid effects. The relationship between cannabinoid and nociceptin/NOP system is yet poorly explored. In this study, we used the neuroblastoma SH-SY5Y cell line to investigate the effect of delta-9-tetrahydrocannabinol (∆-THC) on nociceptin/NOP system. Results revealed that the exposure to ∆-THC (100, 150, and 200 nM) for 24 h produces a dose-dependent NOP receptor B down-regulation. Moreover, ∆-THC caused a dose-dependent decrease in NOP mRNA levels. The selective cannabinoid receptor CB1 antagonist AM251 (1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl- N-1-piperidinyl-1H-pyrazole-3-carboxamide) reduces both effects, suggesting that ∆-THC activation of CB1 receptor is involved in the observed effects. These data show evidence of a cross-talk between NOP and CB1 receptors, thus suggesting a possible interplay between cannabinoid and nociceptin/NOP system. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
35. Ethanol and acetaldehyde exposure induces specific epigenetic modifications in the prodynorphin gene promoter in a human neuroblastoma cell line.
- Author
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D'Addario, Claudio, Johansson, Sofia, Candeletti, Sanzio, Romualdi, Patrizia, Ögren, Sven Ove, Terenius, Lars, and Ekström, Tomas J.
- Abstract
Ethanol alters neural activity through interaction with multiple neurotransmitters and neuromodulators. The endogenous opioid system seems to play a key role, since the opioid receptor antagonist naltrexone (ReVia
® ) attenuates craving for alcohol. We recently reported that ethanol and acetaldehyde, the first product of ethanol metabolism, affect transcription of opioid system genes in human SH-SY5Y neuroblastoma cells. In the current study, potential epigenetic mechanisms were investigated to clarify these effects on prodynorphin gene expression. DNA methylation was analyzed by bisulfite pyrosequencing, and chromatin immunoprecipitation was used to assess putative specific histone modifications at the prodynorphin gene promoter. The results demonstrated a temporal relationship between selective chromatin modifications induced by ethanol and acetaldehyde and changes in prodynorphin gene expression quantitated by real-time qPCR. DNA methylation was not altered in any of the experimental conditions used. The epigenetic changes may precede gene transcription, and histone modifications might keep the prodynorphin gene in a poised state for later reactivation. A link has been observed between gene expression alterations and selective epigenetic modulation in the prodynorphin promoter region, demonstrating a specificity of the changes induced by ethanol and acetaldehyde. The latter may be mediating ethanol effects at the genomic level.—D'Addario, C., Johansson, S., Candeletti, S., Romualdi, P., Ogren, S. O., Terenius, L., Ekstrom,T. J. Ethanol and acetaldehyde exposure induces specific epigenetic modifications in the prodynorphin gene promoter in a human neuroblastoma cell line. [ABSTRACT FROM AUTHOR]- Published
- 2011
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36. Regulation of opioid gene expression in the rat brainstem by 3,4-methylenedioxymethamphetamine (MDMA): role of serotonin and involvement of CREB and ERK cascade.
- Author
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Benedetto, Manuela, Bastías Candia, Sussy del Carmen, D'Addario, Claudio, Porticella, Elena, Cavina, Chiara, Candeletti, Sanzio, and Romualdi, Patrizia
- Abstract
The amphetamine analogue 3,4-methylendioxymetamphetamine (MDMA, Ecstasy) causes complex adaptations at the molecular and cellular levels altering the activity of different brain neurotransmitters. The present study aims to verify the effects of single and repeated injections of MDMA on dynorphin and nociceptin systems gene regulation in the brainstem, an area rich in neurons containing serotonin. Both acute and chronic (twice a day for 7 days) MDMA (8 mg/kg) induced a marked increase in prodynorphin mRNA levels as well as in cAMP response element-binding protein (CREB) and extracellular signal-regulated kinase-1/2 (ERK1/2) phosphorylation, without causing any effect on kappa opioid receptor or nociceptin system (both pronociceptin and its receptor) genes expression, in this brain region. The blockade of 5HT1/5HT2 receptors by methysergide abolished the acute MDMA-induced increase in prodynorphin. Moreover, the concomitant chronic administration of both methysergide and MDMA (7 days) induced a significant increase in all the dynorphin or nociceptin system genes expression and in CREB and ERK phosphorylation. Our data suggest the involvement of dynorphin in the effects evoked by MDMA in the brainstem, possibly via CREB and ERK1/2 cascade activation, since the ERK inhibitor PD98059 prevented the MDMA-induced prodynorphin gene expression, and, acutely, also through the involvement of serotoninergic mechanisms. Chronically, it is also possible to hypothesize a general inhibitor role of serotonin in the effects evoked by MDMA. Moreover, these findings strengthen the hypothesis, already proposed, of a neuroprotective role for both CREB and dynorphin. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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37. Brain Interstitial Nociceptin/Orphanin FQ Levels are Elevated in Parkinson's Disease.
- Author
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Marti, Matteo, Sarubbo, Silvio, Latini, Francesco, Cavallo, Michele, Eleopra, Roberto, Biguzzi, Sara, Lettieri, Christian, Conti, Carlo, Simonato, Michele, Zucchini, Silvia, Quatrale, Rocco, Sensi, Mariachiara, Candeletti, Sanzio, Romualdi, Patrizia, and Morari, Michele
- Abstract
Expression and release of nociceptin/orphanin FQ (N/OFQ) are elevated in the substantia nigra reticulata of 6-hydroxydopamine-hemilesioned rats, suggesting a pathogenic role for N/OFQ in Parkinson's disease. In this study, we investigated whether elevation of N/OFQ expression in 6-hydroxydopamine-hemilesioned rats selectively occurs in substantia nigra and whether hypomotility following acute haloperidol administration is accompanied by a rise in nigral N/OFQ levels. Moreover, to prove a link between N/OFQ and idiopathic Parkinson's disease in humans, we measured N/OFQ levels in the cerebrospinal fluid of parkinsonian patients undergoing surgery for deep brain stimulation. In situ hybridization demonstrated that dopamine depletion was associated with increase of N/OFQ expression in substantia nigra (compacta +160%, reticulata +105%) and subthalamic nucleus (+45%), as well as reduction in caudate putamen (−20%). No change was observed in globus pallidus, nucleus accumbens, thalamus, and motor cortex. Microdialysis coupled to the bar test allowed to demonstrate that acute administration of haloperidol (0.8 and 3 mg/kg) increased nigral N/OFQ levels (maximally of +47% and +53%, respectively) in parallel with akinesia. A correlation with preclinical studies was found by analyzing N/OFQ levels in humans. Indeed, N/OFQ levels were found to be ∼3.5-fold elevated in the cerebrospinal fluid of parkinsonian patients (148 fmol/ml) compared with nonparkinsonian neurologic controls (41 fmol/ml). These data represent the first clinical evidence linking N/OFQ to idiopathic Parkinson's disease in humans. They strengthen the pathogenic role of N/OFQ in the modulation of parkinsonism across species and provide a rationale for developing N/OFQ receptor antagonists as antiparkinsonian drugs. © 2010 Movement Disorder Society [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
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38. Interplay between Prokineticins and Histone Demethylase KDM6A in a Murine Model of Bortezomib-Induced Neuropathy.
- Author
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Rullo, Laura, Franchi, Silvia, Amodeo, Giada, Caputi, Francesca Felicia, Verduci, Benedetta, Losapio, Loredana Maria, Sacerdote, Paola, Romualdi, Patrizia, and Candeletti, Sanzio
- Subjects
DEMETHYLASE ,GENETIC regulation ,NEUROPATHY ,ANIMAL disease models ,LABORATORY mice ,GLYCINE receptors ,CHEMOKINES - Abstract
Chemotherapy-induced neuropathy (CIN) is a major adverse effect associated with many chemotherapeutics, including bortezomib (BTZ). Several mechanisms are involved in CIN, and recently a role has been proposed for prokineticins (PKs), a chemokine family that induces proinflammatory/pro-algogen mediator release and drives the epigenetic control of genes involved in cellular differentiation. The present study evaluated the relationships between epigenetic mechanisms and PKs in a mice model of BTZ-induced painful neuropathy. To this end, spinal cord alterations of histone demethylase KDM6A, nuclear receptors PPARα/PPARγ, PK2, and pro-inflammatory cytokines IL-6 and IL-1β were assessed in neuropathic mice treated with the PK receptors (PKRs) antagonist PC1. BTZ treatment promoted a precocious upregulation of KDM6A, PPARs, and IL-6, and a delayed increase of PK2 and IL-1β. PC1 counteracted allodynia and prevented the increase of PK2 and of IL-1β in BTZ neuropathic mice. The blockade of PKRs signaling also opposed to KDM6A increase and induced an upregulation of PPAR gene transcription. These data showed the involvement of epigenetic modulatory enzymes in spinal tissue phenomena associated with BTZ painful neuropathy and underline a role of PKs in sustaining the increase of proinflammatory cytokines and in exerting an inhibitory control on the expression of PPARs through the regulation of KDM6A gene expression in the spinal cord. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
39. Chronic Δ9 -Tetrahydrocannabinol During Adolescence Provokes Sex-Dependent Changes in the Emotional Profile in Adult Rats: Behavioral and Biochemical Correlates.
- Author
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Rubino, Tiziana, Vigano, Daniela, Realini, Natalia, Guidali, Cinzia, Braida, Daniela, Capurro, Valeria, Castiglioni, Chiara, Cherubino, Francesca, Romualdi, Patrizia, Candeletti, Sanzio, Sala, Mariaelvina, and Parolaro, Daniela
- Abstract
Few and often contradictory reports exist on the long-term neurobiological consequences of cannabinoid consumption in adolescents. The endocannabinoid system plays an important role during the different stages of brain development as cannabinoids influence the release and action of different neurotransmitters and promote neurogenesis. This study tested whether long-lasting interference by cannabinoids with the developing endogenous cannabinoid system during adolescence caused persistent behavioral alterations in adult rats. Adolescent female and male rats were treated with increasing doses of Δ
9 -tetrahydrocannabinol (THC) for 11 days (postnatal day (PND) 35–45) and left undisturbed until adulthood (PND 75) when behavioral and biochemical assays were carried out. CB1 receptor level and CB1/G-protein coupling were significantly reduced by THC exposure in the amygdala (Amyg), ventral tegmental area (VTA) and nucleus accumbens (NAc) of female rats, whereas male rats had significant alterations only in the amygdala and hippocampal formation. Neither female nor male rats showed any changes in anxiety responses (elevated plus maze and open-field tests) but female rats presented significant ‘behavioral despair’ (forced swim test) paralleled by anhedonia (sucrose preference). In contrast, male rats showed no behavioral despair but did present anhedonia. This different behavioral picture was supported by biochemical parameters of depression, namely CREB alteration. Only female rats had low CREB activity in the hippocampal formation and prefrontal cortex and high activity in the NAc paralleled by increases in dynorphin expression. These results suggest that heavy cannabis consumption in adolescence may induce subtle alterations in the emotional circuit in female rats, ending in depressive-like behavior, whereas male rats show altered sensitivity to rewarding stimu. [ABSTRACT FROM AUTHOR]- Published
- 2008
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- View/download PDF
40. Kainic Acid Down-regulates NOP Receptor Density and Gene Expression in Human Neuroblastoma SH-SY5Y Cells.
- Author
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Cannarsa, Rosalia, Landuzzi, Daniela, Cavina, Chiara, Candeletti, Sanzio, and Romualdi, Patrizia
- Abstract
Nociceptin (N/OFQ) is involved in neuronal excitability and in certain types of seizures. Kainate-induced seizures are associated with increased N/OFQ release in the rat thalamus and hippocampus, causing down-regulation of the N/OFQ receptor (NOP). In this study, we used the neuroblastoma SH-SY5Y cell line as a model to investigate the effects of kainate on NOP receptor density and gene expression. Exposure to kainate (10–50 μM) for 3 h did not affect NOP receptor density. In contrast, a NOP B
max down-regulation was detected in cells exposed to 10 μM kainate for both 6 and 24 h. Moreover, our data show that kainate causes a decrease in NOP mRNA levels after 3, 6, and 24 h, an effect blocked by the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). These findings show that kainate is able to affect the NOP system, both at biosynthesis and receptor density levels in SH-SY5Y cells, and that the kainate ionotropic receptor can contribute to the regulation of the NOP receptor. These data are in agreement with data obtained in vivo and provide new evidence concerning the existence of a cross-talk between NOP and kainate receptors, leading to an interplay between glutamate and N/OFQ circuits. [ABSTRACT FROM AUTHOR]- Published
- 2008
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- View/download PDF
41. Chronic cocaine produces decreases in N/OFQ peptide levels in select rat brain regions.
- Author
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Romualdi, Patrizia, Benedetto, Manuela, D'Addario, Claudio, Collins, Stephanie, Wade, Dean, Candeletti, Sanzio, and Izenwasser, Sari
- Abstract
The interaction of opioids and stimulants is well established; however, the mechanisms that underlie the role that opioid receptors play in psychostimulant action are not. Nociceptin/orphaninFQ (N/OFQ), the endogenous agonist at NOP receptors, attenuates the behavioral effects of cocaine. The effects of cocaine on N/OFQ were examined in rats using immunoautoradiographic and RIA techniques. Chronic administration of cocaine decreased N/OFQ in medial regions of the caudate putamen, the nucleus accumbens shell, and the substantia nigra. These studies show that N/OFQ levels are altered by treatment with cocaine. Furthermore the changes in N/OFQ parallel those seen for K-opioid receptors, suggesting that the interactions between cocaine and these systems might be similar. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
42. Effects of prolonged treatment with the opiate tramadol on prodynorphin gene expression in rat CNS.
- Author
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Candeletti, Sanzio, Lopetuso, Giuseppe, Cannarsa, Rosalia, Cavina, Chiara, and Romualdi, Patrizia
- Abstract
A low abuse liability is reported for tramadol, an analgesic drug centrally acting through either opioid or nonopioid mechanisms. In this paper, we evaluated the effects of the repeated administration (7 d) of different doses of tramadol (10, 20, and 80 mg/kg, intraperitoneally) on the opioid precursor prodynorphin biosynthesis, in comparison with morphine (10 mg/kg, intraperitoneally), in the rat central nervous system (CNS). Northern analysis showed that morphine and tramadol produced different effects. While morphine caused a down-regulation of prodynorphin mRNA levels in all investigated areas (hypothalamus, hippocampus, and striatum), tramadol did not cause any significant change in the striatum, and did not decrease prodynorphin biosynthesis in the hypothalamus and in the hippocampus, at nontoxic doses (10 and 20 mg/kg). The highest dose of tramadol (80 mg/kg) decreased prodynorphin mRNA levels in the hypothalamus and the hippocampus but not in the striatum. These data give some information on tramadol effects at molecular level in the CNS. They indicate that the alterations of prodynorphin gene expression caused by tramadol and morphine show a different pattern that may be related to the different abuse potential of the two analgesic drugs. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
43. Blockade of Nociceptin/Orphanin FQ Transmission Attenuates Symptoms and Neurodegeneration Associated with Parkinson's Disease.
- Author
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Marti, Matteo, Mela, Flora, Fantin, Martina, Zucchini, Silvia, Brown, Jeffrey M., Witta, Jassir, Di Benedetto, Manuela, Buzas, Beata, Reinscheid, Rainer K., Salvadori, Severo, Guerrini, Remo, Romualdi, Patrizia, Candeletti, Sanzio, Simonato, Michele, Cox, Brian M., and Morari, Michele
- Subjects
NOCICEPTORS ,NEURODEGENERATION ,PARKINSON'S disease ,NEUROPEPTIDES ,MENTAL depression ,HYPOKINESIA - Abstract
The opioid-like neuropeptide nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) are expressed in the substantia nigra (SN), a brain area containing dopamine neurons that degenerate in Parkinson's disease. Endogenous N/OFQ facilitates nigral glutamate release and inhibits nigrostriatal dopamine transmission and motor behavior. Here, we present evidence suggesting that endogenous N/OFQ may contribute to Parkinson's disease. Pharmacological blockade of the SN N/OFQ-NOP receptor system attenuated parkinsonian-like akinesia/ hypokinesia in 6-hydroxydopamine hemilesioned or haloperidol-treated rats, whereas deletion of the NOP receptor gene conferred mice partial protection from haloperidol-induced motor depression. The antiparkinsonian action of NOP receptor antagonists was associated with reduction of glutamate release in the SN. In 6-hydroxydopamine hemilesioned rats, enhancement of N/OFQ expression and release was detected in the lesioned compared with the unlesioned SN, indicating that parkinsonism may be associated with overactivation of the N/OFQ-NOP receptor system in the SN. Finally, deletion of the N/OFQ gene conferred mice partial protection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of SN dopamine neurons. Based on these data, we propose that NOP receptor antagonists may represent a novel approach for combined (symptomatic and neuroprotective) therapy of Parkinson's disease. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
44. Kainate seizures increase nociceptin/orphanin FQ release in the rat hippocampus and thalamus: a microdialysis study.
- Author
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Aparicio, Liliana Carmona, Candeletti, Sanzio, Binaschi, Anna, Mazzuferi, Manuela, Mantovani, Simona, Benedetto, Manuela Di, Landuzzi, Daniela, Lopetuso, Giuseppe, Romualdi, Patrizia, and Simonato, Michele
- Subjects
HIPPOCAMPUS (Brain) ,LIMBIC system ,THALAMUS ,BRAIN ,MICRODIALYSIS ,RADIOIMMUNOASSAY - Abstract
The neuropeptide nociceptin/orphanin FQ (N/OFQ) has been suggested to play a facilitatory role in kainate seizure expression. Furthermore, mRNA levels for the N/OFQ precursor are increased following kainate seizures, while its receptor (NOP) density is decreased. These data suggest increased N/OFQ release. To obtain direct evidence that this is the case, we have developed a microdialysis technique, coupled with a sensitive radioimmunoassay, that allows measurement of N/OFQ release from the hippocampus and thalamus of awake, freely moving animals. In both these brain areas, the spontaneous N/OFQ efflux decreased by approximately 50% and 65% when Ca
2+ was omitted and when tetrodotoxin was added to the perfusion medium, respectively. Perfusion of the dialysis probe with high K+ increased N/OFQ release (approximately threefold) in a Ca2+ -dependent and tetrodotoxin-sensitive manner. Kainate seizures caused a twofold increase in N/OFQ release followed, within 3 h, by a return to baseline levels. Approximately 5 h after kainate, a late increase in N/OFQ release was observed. On the following day, when animals were having only low grade seizures, N/OFQ release was not significantly different from normal. These phenomena were observed with similar patterns in the hippocampus and in the thalamus. The present data indicate that acute limbic seizures are associated with increased N/OFQ release, which may prime the molecular changes described above, i.e. cause down-regulation of NOP receptors and activation of N/OFQ biosynthesis. [ABSTRACT FROM AUTHOR]- Published
- 2004
- Full Text
- View/download PDF
45. Differential time course of effects of κ-opioid agonist treatment on dynorphin a levels and κ-opioid receptor density.
- Author
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D’Addario, Claudio, Benedetto, Manuela, Izenwasser, Sari, Candeletti, Sanzio, and Romualdi, Patrizia
- Abstract
The effects of κ-opioid agonist treatment on κ-opioid receptor density and on dynorphin A levels in the rat brain were studied. Rats were treated with the selective κ-opioid agonist U-69593 or vehicle for 5 d. Dynorphin A levels and κ-opioid receptor binding were measured on day 8 (3 d after the last injection) or 22 (17 d after the last injection). On day 8, κ-opioid receptor density was increased in the hypothalamus of rats treated with U-69593; there were no changes in the frontal cortex or caudate putamen. In contrast, there was an increase in dynorphin A levels in the frontal cortex and no changes in hypothalamus and caudate putamen in response to U-69593. On day 22, B
max was decreased in frontal cortex and caudate putamen of U-69593-treated rats, whereas dynorphin A levels were increased in the caudate putamen and in the frontal cortex. These findings suggest that κ-opioid receptor agonist treatment has long-term, continually changing effects on the κ-opioid system. [ABSTRACT FROM AUTHOR]- Published
- 2004
- Full Text
- View/download PDF
46. Role of serotonin on cocaine-mediated effects on prodynorphin gene expression in the rat brain.
- Author
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Di Benedetto, Manuela, D’Addario, Claudio, Collins, Stephanie, Izenwasser, Sari, Candeletti, Sanzio, and Romualdi, Patrizia
- Abstract
The effect of the selective serotonin uptake inhibitor fluoxetine was examined on prodynorphin gene expression. Fluoxetine or vehicle was infused continuously for 7 d via osmotic minipumps into male rats. Northern blot analysis showed significant increases in prodynorphin gene expression in the hypothalamus (171% of controls) and significant decreases in the caudate putamen and nucleus accumbens (62% and 70% of controls, respectively). There were no significant changes in the hippocampus. Thus, chronic inhibition of serotonin uptake can regulate prodynorphin gene expression in the hypothalamus, caudate putamen, and nucleus accumbens. Fluoxetine effects were also evaluated in rats treated with p-chloroamphetamine (PCA), a neurotoxin that depletes serotonin. Because we previously reported that continuous infusion of cocaine for 7 d (which inhibits dopamine, serotonin, and norepinephrine uptake), or GBR 12909 (a selective dopamine uptake inhibitor), produced significant decreases in the hypothalamus and cocaine also produced a significant increase in prodynorphin gene expression in caudate putamen, regulation of prodynorphin gene expression by fluoxetine is suggested to be different from that by cocaine. Because neither a selective dopamine uptake inhibitor nor a selective serotonin uptake inhibitor produced the same effect as cocaine in the caudate putamen, this effect is likely regulated by the inhibition of norepinephrine uptake, by a combination of effects on two or three neurotransmitter transporters, or by a mechanism unrelated to transporter inhibition. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
47. Limbic seizures increase pronociceptin mRNA levels in the thalamic reticular nucleus.
- Author
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Bregola, Gianni, Candeletti, Sanzio, Romualdi, Patrizia, and Simonato, Michele
- Published
- 1999
- Full Text
- View/download PDF
48. Distinguishable effects of intrathecal dynorphins, somatostatin, neurotensin and s-calcitonin on nociception and motor function in the rat.
- Author
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Spampinato, S, Romualdi, P, Candeletti, S, Cavicchini, E, Ferri, S, Spampinato, Santi, Romualdi, Patrizia, Candeletti, Sanzio, Cavicchini, Emanuela, and Ferri, Sergio
- Published
- 1988
- Full Text
- View/download PDF
49. Dysregulation of Nociceptin/Orphanin FQ and Dynorphin Systems in the Extended Amygdala of Alcohol Preferring Marchigian Sardinian (msP) Rats.
- Author
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Caputi, Francesca Felicia, Stopponi, Serena, Rullo, Laura, Palmisano, Martina, Ubaldi, Massimo, Candeletti, Sanzio, Ciccocioppo, Roberto, Romualdi, Patrizia, and Ventura, Carlo
- Subjects
NOCICEPTIN ,BRAIN-derived neurotrophic factor ,DYNORPHINS ,ALCOHOLISM ,OPIOID peptides ,AMYGDALOID body ,ALCOHOL drinking - Abstract
Previous studies have shown that genetically selected Marchigian Sardinian alcohol-preferring (msP) rats consume excessive amounts of ethanol to self-medicate from negative moods and to relieve innate hypersensitivity to stress. This phenotype resembling a subset of alcohol use disorder (AUD) patients, appears to be linked to a dysregulation of the equilibrium between stress and antistress mechanisms in the extended amygdala. Here, comparing water and alcohol exposed msP and Wistar rats we evaluate the transcript expression of the anti-stress opioid-like peptide nociceptin/orphanin FQ (N/OFQ) and its receptor NOP as well as of dynorphin (DYN) and its cognate κ-opioid receptor (KOP). In addition, we measured the transcript levels of corticotropin-releasing factor (CRF), CRF receptor 1 (CRF1R), brain-derived neurotrophic factor (BDNF) and of the tropomyosin receptor kinase B receptor (Trk-B). Results showed an innately up-regulation of the CRFergic system, mediating negative mood and stress responses, as well as an inherent up-regulation of the anti-stress N/OFQ system, both in the amygdala (AMY) and bed nucleus of the stria terminalis (BNST) of msP rats. The up-regulation of this latter system may reflect an attempt to buffer the negative condition elicited by the hyperactivity of pro-stress mechanisms since results showed that voluntary alcohol consumption dampened N/OFQ. Alcohol exposure also reduced the expression of dynorphin and CRF transmissions in the AMY of msP rats. In the BNST, alcohol intake led to a more complex reorganization of these systems increasing receptor transcripts in msP rats, along with an increase of CRF and a decrease of N/OFQ transcripts, respectively. Moreover, mimicking the effects of alcohol in the AMY we observed that the activation of NOP receptor by intracerebroventricular administration of N/OFQ in msP rats caused an increase of BDNF and a decrease of CRF transcripts. Our study indicates that both stress and anti-stress mechanisms are dysregulated in the extended AMY of msP rats. The voluntary alcohol drinking, as well as NOP agonism, have a significant impact on neuropeptidergic systems arrangement, bringing the systems back to normalization. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
50. On the Role of Peripheral Sensory and Gut Mu Opioid Receptors: Peripheral Analgesia and Tolerance.
- Author
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Fürst, Susanna, Zádori, Zoltán S., Zádor, Ferenc, Király, Kornél, Balogh, Mihály, László, Szilvia B., Hutka, Barbara, Mohammadzadeh, Amir, Calabrese, Chiara, Galambos, Anna Rita, Riba, Pál, Romualdi, Patrizia, Benyhe, Sándor, Timár, Júlia, Schmidhammer, Helmut, Spetea, Mariana, and Al-Khrasani, Mahmoud
- Subjects
OPIOID receptors ,ANALGESIC effectiveness ,ANALGESIA ,SENSORY neurons ,OPIOID analgesics - Abstract
There is growing evidence on the role of peripheral µ-opioid receptors (MORs) in analgesia and analgesic tolerance. Opioid analgesics are the mainstay in the management of moderate to severe pain, and their efficacy in the alleviation of pain is well recognized. Unfortunately, chronic treatment with opioid analgesics induces central analgesic tolerance, thus limiting their clinical usefulness. Numerous molecular mechanisms, including receptor desensitization, G-protein decoupling, β-arrestin recruitment, and alterations in the expression of peripheral MORs and microbiota have been postulated to contribute to the development of opioid analgesic tolerance. However, these studies are largely focused on central opioid analgesia and tolerance. Accumulated literature supports that peripheral MORs mediate analgesia, but controversial results on the development of peripheral opioid receptors-mediated analgesic tolerance are reported. In this review, we offer evidence on the consequence of the activation of peripheral MORs in analgesia and analgesic tolerance, as well as approaches that enhance analgesic efficacy and decrease the development of tolerance to opioids at the peripheral sites. We have also addressed the advantages and drawbacks of the activation of peripheral MORs on the sensory neurons and gut (leading to dysbiosis) on the development of central and peripheral analgesic tolerance. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
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